Abstract

Aim: The main goals of this chart-review study were to examine the rate of tachyphylaxis during treatment of dysthymia with antidepressants, to compare the incidence of tolerance during trials of selective serotonin reuptake inhibitors (SSRI) and non-SSRI and to give descriptive analysis of the cases of tachyphylaxis.

Methods: The retrospective naturalistic chart review study included 52 cases of successfully treated (with different antidepressants) patients suffering from dysthymia. The overall number of the cases of tolerance to antidepressants were registered as well as the rate of these phenomena in the groups treated with SSRI and non-SSRI.

Results: The cases of tolerance/tachyphylaxis were observed in 12 patients (23% of patients) and in 13 trials (22.4% of trials). All cases of tolerance occurred during monotherapy. No cases of tachyphylaxis were observed in the non-SSRI group while in the SSRI group, tolerance at some stage of the treatment was detected in 41.9% of the successful cases (P < 0.001).

Conclusion: During the treatment of dysthymia with antidepressants in the SSRI group, tachyphylaxis/tolerance might be observed in a relatively in high proportion of cases.

THE PHARMACOLOGIC TERM ‘tachyphylaxis’ is defined as an appearance of progressive decrease in response to a given dose after repetitive administration of a pharmacologically or physiologically active substance.1 In some studies, tachyphylaxis (or ‘poop-out’) is defined as a relapse or recurrence of an episode of major depression after full recovery from a major depressive episode despite continued treatment with a previously effective antidepressant;2 other studies characterize the phenomenon as a return of depressed mood, apathy or decreased motivation (described by patients as ‘the blahs’), fatigue, dullness in cognitive function, sleep disturbance, weight gain, and sexual dysfunction.3 Patients frequently report the some deterioration they felt after initially achieving remission on the antidepressant, but not as bad as they felt before treatment when they were in an episode of major depression.4 Although in most clinical studies the term tachyphylaxis is used, the term ‘tolerance’ could be more correct from a pharmacologic point of view.5 While the term ‘antidepressant tachyphylaxis’ stresses mostly the possibility of habituation/sensitization mechanisms, the term tolerance is much more comprehensive and includes the mechanisms of pharmacodynamic tolerance, pharmacokinetic tolerance, increase in disease severity, change in disease pathogenesis, depleted effector substance, prominent increase of drug serum level and existence of detrimental metabolite.6 In the current report the terms tachyphylaxis and tolerance have been used interchangeably.

Over a 2-week period, the Rothschild Scale for Antidepressant Tachyphylaxis (RSAT)4 was used to assess disturbances (energy level, motivation and interest, cognitive functioning, sleep, and sexual functioning) in patients on antidepressants who do not currently fulfill the criteria for an episode of major depression and had a previous good response to antidepressant therapy. The frequency of antidepressant tolerance is still unknown and is reportedly from 9% to 33% of patients in published trials.6 Some data suggest that rates of tachyphylaxis are significantly lower with the dual reuptake inhibitors and tricyclic antidepressants (TCA) compared to rates of tachyphylaxis with SSRI,7 but the issue is still far from clear.

Most of the studies concerning antidepressants' tachyphylaxis were performed during treatment of major depressive disorder or bipolar depression. Very little is known about the possible tolerance in treatment of other depressive conditions, including dysthymia. According to DSM-IV-R8 for diagnosis of dysthymia, at least two of the following symptoms are compulsory: (i) change in appetite (increase or decrease); (ii) change in sleep pattern (increase or decrease); (iii) fatigue or low energy; (iv) low self-esteem; (v) decrease in concentration or inductiveness; and (vi) feelings of hopelessness. The symptoms must be presented for at least a 2-year period for adults and for 1 year for adolescents. While brief periods of normal mood can be observed during this 2-year period, the clinical signs are never absent for more than 2 consecutive months. Dysthymic disorder is described as a semichronic, smoldering mood disorder with a waxing and waning course9 that can affect from 3% to 6% of the general population (life-time prevalence).10,11 While some authors are skeptical about the effectiveness of antidepressants in the treatment of dysthymia,12 others have reported much more favorable results.13 As far as antidepressants are used extensively for treatment of dysthymia, the issue of the supposed loss of their effectiveness remains of great importance.

The main goals of this chart-review study were: (i) to examine the rate of tachyphylaxis during antidepressants' treatment of dysthymia; (ii) to compare the incidence of tolerance during SSRI and non-SSRI trials; (iii) to give a descriptive analysis of the cases of tachyphylaxis. The relatively high rate of tachyphylaxis was supposed, especially for SSRI-treated patients.

METHODS

Subjects

The detailed computerized files of the private outpatients treated between 2001 and 2010 were evaluated. Among all files (n = 1611), 142 cases (8.8%) diagnosed with dysthymia (according to DSM-IV criteria) were detected. The cases with full therapeutic response (clinical impression of complete remission or very minimal residual symptoms) for at least 3 consecutive months were selected. The additional inclusion criteria were: minimum of 6-month follow-up period with at least three follow-up meetings with the patient, a high level of patient cooperation and adherence to the treatment, no comorbid substance abuse, and severe personality disorders or prominent physical morbidity. Due to unclear data about total duration of illness and previous medication trials in some of the cases, this information was not included in the survey. Given the substantial overlap between anxiety and dysthymia, the differential diagnosis was not easy, but the patients with obvious and distinct anxiety disorders, such as obsessive–compulsive disorder, panic attacks and post-traumatic stress disorder, were excluded from the study. Although the Rothschild Scale for Antidepressant Tachyphylaxis4 was not used in complete form, tachyphylaxis was diagnosed based on the criteria of RSAT with the appearance of at least one of the following symptoms: apathy or decreased motivation, fatigue, dullness in cognitive function, sleep disturbance, weight gain, and sexual dysfunction for a minimum of 2 weeks after full response to antidepressants for a minimum of 3 consecutive months. As members of the Orthodox religious community, most of the patients included in the study were under traditional rabbis' counseling, which included elements of cognitive behavioral therapy, supportive and directive psychotherapy.

Data collection and analysis

Computer-generated data were downloaded into Microsoft Excel workbooks. Routine sample descriptive statistics were applied to the demographic data. The χ2 statistic was used to examine the correlation between the two variables.

RESULTS

Out of 142 cases diagnosed with dysthymia, 52 patients (36.6%) met the criteria for response, length and frequency of follow up, adherence and lack of comorbidity; 28 (53.8%) were male and 24 were (46.2%) female. The majority of the examined patients (73%) were Orthodox Jews. Age varied from 18 to 79 years old; mean 31.36 ± 15.17 years. The length of follow up was from 6 to 86 months (mean 22.61 ± 17.3) with mean 4.4 meetings. In the studied group, 83 trials with different antidepressants were described: 74 trials were monotherapy and in nine trials the antidepressants were used in combination or with augmentation. In the cases of monotherapy, 48 trials were with different SSRI (escitalopram, fluoxetine, paroxetine, citalopram, sertraline), 14 trials were with serotonin norepinephrine reuptake inhibitors (SNRI) (duloxetine, venlafaxine, milnacipran), and four cases were with TCA (amitriptyline, clomipramine, maprotiline, imipramine). In eight trials, antidepressants with another mechanism of action (bupropion, mirtazapine, reboxetine) were chosen for the monotherapy. The SSRI were the first choice in 75 trials (90.3%); in eight trials, the SNRI or other medications were the first choice due to a history of side-effects or lack of effect of the SSRI. In nine trials with combined use of medications, the following combinations were prescribed. As a result of 58 antidepressant trials the full therapeutic responses for at least 3 consecutive months were achieved and these trials were defined as successful: 51 trials were monotherapy and seven trials were combined use. In 31 successful trials SSRI were used as monotherapy, SNRI were used in 12 trials, TCA were used in four trials and another antidepressant (mirtazapine) was used in four trials. In seven trials, response was achieved using combined therapy SSRI + TCA, bupropion + TCA and bupropion + lamotrigine. The cases of tolerance/ tachyphylaxis were observed in 12 patients (23% of patients) and in 13 trials (22.4% of trials). All cases of tolerance occurred during the monotherapy. The monotherapy trials of patients that finally fully responded were divided into two groups: SSRI trials and non-SSRI trials (SNRI, TCA and other). Although the rate of successful trials in the non-SSRI group was higher than that in the SSRI group (76.9.2% vs 64.6%) the difference was not statistically significant. The picture was quite dissimilar concerning the cases of tachyphylaxis: no cases were observed in the non-SSRI group while in the SSRI group in 13 cases (41.9.1% of successful trials), tachyphylaxis at some stage of the treatment was reported (χ2 = 11.256, P = 0.00079). The description of the cases of tolerance occurring in the patients, summarized in Table 1, shows great variability in the baseline demographic factors, time of appearance of tolerance, therapeutic strategies and results of treatment of the phenomena.

Table 1. Descriptive analysis of the cases of tachyphylaxis

n

Sex

Age

Time of follow up (months)

Length of good response before appearance of tachyphylaxis (months)

Medication possibly connected to tachyphylaxis

Method of treating tachyphylaxis

Results of treatment of tachyphylaxis

(+++) full remission or very good response; (++) good response; (+) partial response; (+/−) questionable response; (−) no response.

1

m

31

23

15

Escitalopram 10 mg

Increase dosage to 20 mg

+++

2

m

18

8

6

Paroxetine 20 mg

Increase dosage to 30 mg

+++

3

m

25

28

24

Escitalopram 30 mg

Decrease dosage to 20 mg

++

4

m

31

36

22

Escitalopram 10 mg

Increase dosage to 15 mg

+++

5

f

33

48

34

Escitalopram 20 mg

Augmentation with amitriptyline 25 mg

+++

6

m

29

36

15-first

Escitalopram 10 mg

Increase dosage to 20 mg

+++ (temporary)

3-second

Escitalopram 20 mg

Shift to venlafaxine 225 mg

+++

7

m

23

33

6

Escitalopram 20 mg

Added cognitive behavioral therapy

+++

8

f

26

22

7

Escitalopram 20 mg

Augmentation with clomipramine 50 mg

+++

9

m

27

20

9

Escitalopram 10 mg

Increase dosage to 20 mg

−

Shift to bupropion 300 mg

−

Augmentation of bupropion with amitriptyline 50 mg

+

10

f

29

12

6

Escitalopram 20 mg

Augmentation with maprotiline 75 mg

+/−

11

m

27

9

6

Escitalopram 20 mg

Augmentation with imipramine 75 mg

++

12

f

20

17

14

Sertraline 100 mg

Increase dosage to 200 mg

−

Shift to milnacipran 100 mg

+++

DISCUSSION

The results of the survey indicated the high possibility of developing tolerance to SSRI antidepressants during treatment of dysthymia. Although the elevated rate of tachyphylactic cases in SSRI-treated patients was hypothesized, the real frequency of the phenomena appeared to be surprisingly high with no such symptoms in the non-SSRI group. Prominent differences between SSRI and other antidepressants concerning the issue of tolerance to medications in major depression were reported in some studies. In a retrospective study, Posternak and Zimmerman7 compared rates of tachyphylaxis of TCA and venlafaxine, which act as dual reuptake inhibitors (though usually in high dosages) versus SSRI. The cohort reported having undergone 326 prior SSRI trials, 47 prior venlafaxine trials, and 35 prior trials with a TCA. Rates of tachyphylaxis were significantly lower with the dual reuptake inhibitors venlafaxine and TCA (3.7%) compared to rates of tachyphylaxis with SSRI (14.1%). Serotonin receptor desensitization has been hypothesized to be the primary actor responsible for the observation of an increased risk for the return of depressive symptoms during long-term treatment with selective serotonin reuptake inhibitors.14 The data of higher frequency of ‘poop out’ effect in SSRI medications compared to the dual reuptake inhibitors in the present study as well as in some others could be seen as an indirect support to this hypothesis. A multiphase, double-blind, placebo-controlled study assessed the efficacy of venlafaxine extended release (ER) during two sequential 1-year maintenance phases (A and B) in patients with recurrent major depressive disorder.15 The maintenance phase A population was comprised of 337 patients (venlafaxine ER [n = 129], fluoxetine [n = 79], placebo [n = 129]), whereas 128 patients (venlafaxine ER [n = 43], fluoxetine [n = 45], placebo [n = 40]) were treated during maintenance phase B. No differences in the probability of experiencing tachyphylaxis were observed between the active treatment groups during either maintenance phase; however, only two medications from the SSRI and SNRI groups were compared and it is still unclear whether a follow up longer than 1 year would generate different results.

The clinical aspects of the theory of tachyphylaxis as ‘stepwise’ receptor desensitization during unipolar major depression were studied by Amsterdam and colleagues.16 The results indicated that the number of prior antidepressant drug exposures was negatively associated with response to initial sertraline therapy and connected to ‘stepwise’ receptor desensitization due to SSRI treatment. Interestingly, in the present study only one case of repetitive tolerance to different doses of escitalopram was described, which could be explained partly by the relatively low dosage (10 mg) of the medication used during the first stage of the treatment.

Some research data indicate that the placebo effect might be of crucial importance in antidepressants' influence in patients with mild or moderate symptoms. In the recently published meta-analysis by Fournier et al.,17 randomized placebo-controlled trials of antidepressants approved by the Food and Drug Administration in the treatment of major or minor depressive disorder were summarized. Conclusions of the study were that the magnitude of benefit of antidepressant medication compared with placebo increases with severity of depression symptoms and may be minimal or non-existent, on average, in patients with mild or moderate symptoms. Rather different results were reported in a meta-analysis concerning the antidepressant treatment of dysthymia.18,19 Fifteen trials were included for the main comparisons. Similar results were obtained in terms of efficacy for different groups of drugs, such as TCA, SSRI, and monoamine oxidase inhibitors (MAOI). The pooled relative risk treatment response was 0.68 (95% CI 0.59–0.78) for TCA, 0.64 (95% CI 0.55–0.74) for SSRI, and 0.59 (95% CI 0.48–0.71) for MAOI. There were no differences in response to active treatment when dysthymia was compared to dysthymia plus major depression or briefer non-major depressive states. The authors' conclusion was that drug treatment appears to be effective in the short-term management of dysthymic disorder. Although seen as a mild–moderate kind of depressive disorder, dysthymia is quite different from lower-symptom-level depressions in its chronic course; chronicity is known to be associated with poor response to placebo.20 Therefore, it may be that the chronic nature of dysthymia explains the advantage of antidepressants over placebo in this condition.

The data concerning the possible role of placebo in appearance of tolerance to antidepressants is sparse and contradictive. Some authors doubt the existence of true tachyphylaxis and attribute the loss of antidepressant response during most cases of maintenance-phase therapy to either non-adherence and/or loss of placebo effect.21,22

The problem of predisposition factors to tachyphylaxis is also far from clear. Summarizing mostly case reports and case series, Byrne and Rothschild6 noted that most of the patients with reported tachyphylaxis were female; the mean age was 42 ± 14 years old, the average length of successful treatment before tolerance appearance was 24 weeks; the average length of remission was 12 weeks. Due to a relatively small absolute number of cases of tachyphylaxis and their heterogeneity in the present study, the issue of ‘profiling’ of cases' tolerance was rather difficult.

The therapeutic attitudes towards the issue of tachyphylaxis are based more on ‘common sense’ principles than on an evidence-based approach. In the survey about intervention in hypothetical cases of breakthrough depression in the patients taking different antidepressants,23 the most popular choice was increasing the dosage, followed by augmenting with lithium or another antidepressant or changing to a different drug. In the present study the increasing dosage was the first (and most successful) choice for the overcoming of tachyphylaxis (see Table 1). The other tactics used were augmentation, usually of SSRI by TCA, and shift to another group of antidepressants (SNRI and Bupropion). Based on the assumption of the possibility of a ‘therapeutic window’ for some SSRI,24 in one case the tactic of lowering the dosage of escitalopram was successfully applied. Very few publications could be found concerning this method for the treatment of tolerance to SSRI. Cain25 reported that in an open-label study, 23 consecutive outpatients were treated with fluoxetine 20 mg/day for major depression. Four of them failed to sustain initial improvements during 4–8 weeks of treatment (in the absence of apparent side-effects). All four patients responded to a lower dose. The author concluded that apparent difficulty in distinguishing fluoxetine's adverse effects/toxicity (or a ‘therapeutic window’ effect) from underlying depressive symptoms exists; it may suggest the option of lowering the dose in some cases of non-response or tolerance.

Although in most cases of the present survey the strategy of dosage change, switching and augmentation was successful, in the few other trials the results were less positive (see Table 1). Taking into consideration possible mutual mechanisms in their development, tachyphylaxis may contribute to the development of treatment-resistant depression.26

The attitudes to the treatment of antidepressants' tachyphylaxis may also involve non-medication strategies. Cognitive behavioral therapy treatment was added to escitalopram in one case of the discussed report with a positive outcome (Table 1). The possibility of promising results of this technique in the cases of SSRI tolerance was reported by Leykin et al.,27 who assessed the response to antidepressants' therapy and cognitive therapy of patients with a history of prior antidepressant exposure. This observation suggests that cognitive therapy may exert its therapeutic action via a different mechanism than that of antidepressant drug therapy, and may be less affected by the physiological adaptation resulting from prior drug exposure.28

Limitations

As in all retrospective naturalistic chart review studies, this study has numerous and obvious methodological shortcomings. No structured rating scales and questionnaires were used in the evaluation of the patients. In addition, this study had special limitations: as was mentioned, most of the patients came from the Orthodox Jewish community with their specific cultural background and tendency to be treated by the same-sex therapist. As a result, the majority of the patients in the study were male, which does not represent the prevalence of dysthymia in the general population. The compared monotherapy groups were relatively small and the non-SSRI group was heterogeneous in the mechanisms of action of medications. Tachyphylaxis was diagnosed mostly as exacerbation of different somatic features of depression with no clear affective signs. Therefore, there is overlap between those somatic symptoms of tachyphylaxis and the side-effects of SSRI, such as fatigue, weight gain, and sexual dysfunction. Although the side-effects of SSRI and tachyphylaxis are usually different at the time of appearance, the possibility of some misdiagnosing still exists.